Pathogen reduction (PR) represents the ideal preemptive measure to ensure the safety of the blood supply. However, currently available PR technologies have concerns of clinical side effects, limiting their use in the United States. The ideal PR technology should be able to effectively kill a wide variety of pathogens without introducing chemical or biological agents, while retaining the function of the blood products. In this regard, ultrafast lasers represent a promising new chemical-free PR technology. The objective of the proposed studies is to establish an ultrafast laser PR technology for treatment of human plasma, and to determine the physical and molecular mechanisms by which ultrafast lasers kill pathogens. The long-term goal of the proposed studies is to develop an ultrafast laser PR system applicable to plasma, platelets and red blood cells to provide safe transfusion worldwide. The specific aims of the project are: (1) To demonstrate ultrafast laser inactivation of West Nile virus (WNV), a model transfusion-transmitted pathogen; (2) To determine the physical and molecular basis of ultrafast laser-induced inactivation of pathogens; and (3) To determine efficacy of WNV inactivation in a mouse model of plasma transfusion. At the completion of the project, we expect to have made significant progress in the development of a new ultrafast laser technology for PR of plasma, amenable to use in a clinical setting. We anticipate translation of this technology soon to PR of platelets, RBCs, and whole blood in future studies. This technology will also be especially beneficial in military use, such as for emergency transfusions in the field, and low resource areas worldwide where screening and testing are not well established. To our knowledge, this is the first use of ultrafast lasers in the field of transfusio medicine and represents a new medical application for lasers. Continued exploration of this laser PR technology is expected to generate additional applications including sterilization of pharmaceuticals, medical devices, surgical wounds, and surgical instruments, and combating bioterror threats.